Clinical Research and Epidemiology

Robert S. Sandler, M.D., M.P.H.University of North CarolinaChapel Hill, North Carolina

What is epidemiology?

Epidemiology● Study of the distribution and determinants of disease

in populationsClinical epidemiology

● Science of making predictions about individual patients using the tools of epidemiology

History

John Snow Map of cholera cases 1854

History

Epidemiology today

N Engl J Med 2012;367:1704-13

Epidemiology today

N Engl J Med 2012;367:1704-13

Williamsburg

Crown Heights

Borough Park

IBD is a challenge for epidemiologists

Epidemiologic methods work great when● Acute onset illness – cholera, mumps● Point source – Broad Street pump, yeshiva● Rare illness cluster – angiosarcoma of the liver and

vinyl chloride

IBD● Gradual onset in children and adults● Persists for years● No known etiology

Spectrum of epidemiologic research

Disease burden (how many/how much)Etiology risk factors for disease)Diagnosis (evaluation of medical tests)Natural history/prognosis

● What happens to people with disease● Risk factors for disease outcomes

Treatment effects● Intended● Unintended

Methods of clinical research

Observational Studies● Investigators just observe (measure) exposures and

outcomesInterventional Studies

● Investigators assign exposure and measure outcomes (clinical trials of drugs or surgery)

Observational Studies

“You can observe a lot just by watching.” - Yogi Berra

DescriptiveAnalytical

● Cross-sectional● Cohort● Case-control

Descriptive Studies

Burden of Disease● Incidence – how many new cases/time● Prevalence – how many cases currently● Morbidity● Mortality● Costs● Days of work/school lost (disability days)

Descriptive studies

Incidence Prevalence

Prevalence ~ incidence x duration

Analytical studies

Associations between exposures and outcomes● Is smoking (or diet) associated with risk of IBD?● Are specific genes associated with risk of IBD?● Are results of a diagnostic test associated with diagnosis

of IBD?● Is treatment X associated with improvement in Crohn’s

disease activity● Is treatment Y associated with a particular side effect?● Is diet (or other lifestyle factors) associated with IBD

flares?

Cross-sectional studies

Source Population

Sample

Outcome? Exposure?

Exposure and outcome measured at same time

Cross-sectional

Assemble study populationMeasure IBD status (yes/no)Measure smoking (yes/no)Find that people with Crohn’s more likely to smoke

● i.e. smoking (exposure) is associated with CD (outcome)

Advantages: Quick and inexpensiveDisadvantages:

● No temporality● Cannot differentiate cause and effect

Cross-sectionalCCFA Partners: Internet based research study>12,000 individuals with IBD completed an online survey about steroid use and many patient outcomes

Cohort study

Measure exposure

Time

Exposed

Unexposed

Disease

Disease

Study begins here

Baseline

Cohort study

Assemble study population free of diseaseMeasure smoking (yes/no)Follow study population for long timeIdentify those who develop IBDCompare incidence (# new cases) of IBD in smokers vs nonsmokersAdvantages: Can identify temporal relationship, assess causality, determine incidenceDisadvantages:

● Long follow-up needed ($$$$$$$)● If outcome is rare (IBD), need very large population

NSAIDs and Aspirin

Nurses’ Health Study I is a prospective cohort of 121,700 U.S. female registered nurses, aged 30 to 55 years

Aspirin/NSAID use ascertained by self-report

Over 1,295,317 person-years of follow-up

123 cases of CD and 117 cases of UC

Ananthakrishnan, Annals Internal Medicine, 2012

CD UCNSAID > 15 days/month

1.6 (1.0-2.6) 1.9 (1.2-3.0)

Aspirin > 15 days/month

1.0 (0.6-1.5) 1.0 (0.6-1.7)

Case-control study

Time

Exposed?

Exposed?

Disease

NoDisease

Study begins here

Case control studyMatch cases (people with outcome (IBD)) to controlsMeasure prior exposuresCompare exposures in cases and controls

● Are IBD cases more likely to report low fiber intake in past than controls

Advantages: ● Good for rare diseases● More efficient (time and sample size, ↓$$$$)● Can identify temporal relationships

Disadvantages: ● Recall of exposure● Sample selection (cases and controls should arise

from same population)

Case control study of potential risk factors for IBD

Bernstein, Am. J. Gastro, 2006

Cases with CD (n = 364) and UC (n = 217), ages 18-50 yrControls were drawn from Manitoba Health Subjects were administered a multi-item questionnaire

What do statistics tell us?

Magnitude of effectPrecision of resultsStatistical significance - role of chanceStatistical significance not clinical significance

Potential pitfalls: validity and bias

Internal validity: degree to which the study findings reflect the truth

● Bias: Systematic difference between observed findings and the truth

● Chance● Statistics assess role of chance, but do not

address biasExternal validity: degree to which the study findings are applicable to other populations

Types of biasSelection/referral bias

● Distortion in the results due to a difference b/t subjects who participated and those who did not

Measurement bias● Distortion in results due to error in measurement

of the exposure, outcome or both

Outcome(ulcer)

Exposure(smoking)

Confounding

Confounder(alcohol)

DirectEffect

IndirectEffect

Clinical trial

Study population

Intervention ‘A’

Intervention ‘B’

Outcome

Outcome

StandardizedFollow-up

&Co-interventions

What does randomization accomplish?

If treatments are assigned at random, then:● Treatments are unrelated to patient characteristics● Achieves balance among different treatment groups

(same mix of smokers, disease severity, across groups)

● No confounding● Even if confounder not known or measured!

Clinical trial

● 526 patients randomly assigned to receive intravenous ustekinumab or placebo

● Primary outcome (end point) was a clinical response at 6 weeks

Clinical trial

Clinical trial

Why Placebo?

If patients know they are getting a study medication, they may feel betterIf doctors know their patients are getting a medication, they may perceive them as doing better“Double-blind, placebo-controlled”

● All subjects get something● Neither subjects nor investigators know what

Randomization and concealed allocation required to prove efficacyRequired by FDA

Ethical considerations

Honest disagreements exist about the preferred treatment of the condition (equipoise)

● Neither intervention/treatment should be considered inferior, or potentially harmful

The RCT must produce results which are convincing enough to resolve the dispute

● Makes the patients’ participation is worthwhile

Comparative Effectiveness Research

If all we have is placebo controlled trials, then we don’t know

● What medicines are more effective than others● What medicines are safer than others

We need head-to-head comparisons, but● Pharma often not willing to take the risk● FDA not require it

Observational studies?

Clinical Effectiveness Research

Patients who enroll in clinical trials are:● Young to middle aged adults● Free of co-morbidity (other health problems)● Cared for at large research hospitals

What about. . .● Kids● Elderly● Those with other health conditions

Observational studies?

Safety

Clinical trials too small to assess medication safety● 51% of drugs have label changes due to major safety

issues discovered after marketing● 20% of drugs get new “black box” warnings after

marketing● 4% of drugs are ultimately withdrawn for safety

reasons

Incidence

90%

95%

99%5000

4000

3000

2000

1000

1/1001/10 1/1000

Too Small

37

Num

ber o

f exp

osed

Probability of detection

LymphomaREACH n=212CERTIFI n=526

Safety research

Objective: To determine whether initiation of TNF- antagonists compared with immunomodulators is associated with an increased risk of serious infections requiring hospitalizationMethods: Cohort study using de-identified data from insurance companiesFor IBD, TNF- antagonist initiators compared to 6MP/AZA initiators, matched by propensity score

Grijalva, JAMA, 2011

Hospitalization for Infection

No difference in hospitalizations for infectionMean age 58 (versus 35 in SONIC)

What makes a good study

Is there a primary research question?Is the research question important?Is the study design appropriate to the research question?Are the investigators qualified?Is the study population well-defined?Are exposures and outcomes well-defined?Feasible?

● Sample size needed relative to time and budget?● Barriers for recruitment

Burden (for patients and providers) Pool of eligible subjects Competing studies

Ethical?

Review

Conclusion

Broad spectrum of clinical and epidemiological research: burden, etiology, diagnosis, prognosis, treatment effectsMany study designs

● Advantages and disadvantages to each

Focused and highly relevant clinical question essentialMany pitfalls to be considered

● Bias● Ethics● Practical considerations